Malignancy after
Lung Transplantation

May, 2006

Unfortunately, one of the risks of immunosuppression is cancer.  All solid organ transplant recipients are at risk, and lung transplant recipients are among those at highest risk.  According to the International Society for Heart and Lung Transplantation Registry, almost 4% of lung transplant recipients develop a malignancy in the first year; this number increases to 18% by seven years.  There are two potential mechanisms for the development of cancer under the influence of immunosuppression.  The immune system plays a role in detecting early pre-cancerous lesions and eliminates them or limits their growth so that when transplant recipients are immunosuppressed their immune system’s mechanisms to detect cancers or to eliminate them may be impaired.  In addition, there are some viruses that can infect cells and make them proliferate.  One example is human papilloma virus, which is linked to cervical cancer.  Human papilloma virus infection can result in cervical cancer in women who have a normal immune system and can be especially aggressive among those who are immunosuppressed.

Similarly, Epstein-Barr virus has been linked to lymphoma in both immunosuppressed patients and those with apparently normal immune system.  There are several different kinds of lymphoma grouped together because they are malignant proliferations of lymphoid tissues.  The mechanism by which an Epstein-Barr virus infection can lead to lymphoma is thought to be related to an infection of lymphocytes, which immortalizes them and makes them susceptible to genetic mutations and malignant transformation, especially under the influence of immunosuppression.  After transplantation, lymphoma is often called post-transplant lymphoproliferative disease or PTLD because this represents the full spectrum of lymphoid proliferations seen after transplantation, ranging from an infectious mononucleosis-like illness to malignant non-Hodgkin’s lymphoma.

After lung transplantation, PTLD is divided into two broad categories.  In the first year after the transplant, the majority of cases are thoracic.  In other words, they are confined to the transplanted lungs or the mediastinum.  In general, such cases have a good prognosis and a good response to treatment.  There are, however, some cases of multi-focal, or widespread, PTLD in the first year after transplantation.  These cases generally occur in recipients who have never been infected with Epstein-Barr virus and have no immunity to the virus who receive lungs from a donor who has been infected with the virus.  This situation poses a high risk for an early infection with Epstein-Barr virus and disseminated PTLD.  Fortunately, most adults have been infected with Epstein-Barr virus in childhood and have some immunity against it, so this presentation is less common.  In contrast to the early cases of PTLD after lung transplantation, those that manifest after the first year are usually extra-thoracic, often presenting in the abdomen or pelvis with abdominal pain, gastrointestinal bleeding, or non-healing ulcers.  Unfortunately, these late cases have a worse prognosis than the early thoracic cases and are sometimes unrelated to Epstein-Barr virus.

The cornerstone of treatment is de-escalating the immunosuppressive regimen.  The dose of azathioprine or mycophenolate mofetil is usually decreased by 50% or the drug is stopped altogether.  In addition, the target tacrolimus or cyclosporine blood levels are reduced by approximately 50%.  In some cases, especially early thoracic cases, this may be all that is necessary with an adequate response.  However, many early thoracic cases and the majority of late extra-thoracic cases require surgical resection, radiation, chemotherapy, or a combination of the three.  When feasible, surgical resection in conjunction with de-escalation of the immunosuppressive regimen is often curative.  Nonetheless, there are many cases where the tumor is disseminated, especially in the abdomen, and complete resection is not possible.  Traditionally, the most common chemotherapy regimen used is CHOP, which is comprised of cyclophosphamide (cytoxan), adriamycin (hydroxydoxorubicin), vincristine (oncovin) and prednisone.  As might be expected, this regimen carries some potentially serious side effects including nausea, fatigue, hair loss, low white blood counts, and an increased risk of infections.  Recently, a new agent has become available called rituximab, which is a monoclonal antibody to a cell surface molecule present on most lymphomas.  The side effects of rituximab are primarily infusion related and include fever, a flu-like illness, and low blood pressure, but this is generally an easier treatment to tolerate than CHOP.  In some cases, the combination of CHOP and rituximab is given together.

In the first year after lung transplantation, PTLD accounts for approximately 50% of all cancers and skin cancers account for 20%.  On the other hand, after the first year, skin cancers are most common and account for almost 50% of all cancers where PTLD makes up 20% of all late cancers.  The major risk factors for skin cancer for immunosuppressed patients are sun exposure and fair skin and routine dermatologic screening is necessary.  The remaining cancers that complicate the course of most transplant recipients include breast, colon, bladder, and prostate cancer and their treatments are similar to non-immunosuppressed patients.